The long-term goal of this research project is to develop a technique of gene transfer to inhibit acute rejection of venous allografts. Techniques of gene transfer will be used to downregulate class 1 major histocompatibility (MHC-I) self- antigens on porcine venous bypass grafts. The experimental approach will employ a strategy already proven to be highly successful in nature. We plan to use a viral product, specifically the Herpes simplex virus protein ICP47 that has already been shown to inhibit MHC-I expression of infected cells to evade host immune detection. In patients with severe peripheral vascular disease, the best patency rates for distal artery bypasses are achieved with autogenous greater saphenous veins. Not infrequently, this conduit is inadequate in diameter or length, diseased from valvular incompetence, or has been harvested for previous bypass surgery. A cryopreserved venous allograft is one option for such patients who have severe limb threatening ischemia. The relative lack of success of cryopreserved venous allografts has been attributed largely to acute and chronic rejection. Greater understanding of the immune response to vascular allografts is required to improve our current results. Downregulation of MHC-I expression and thereby foreign antigen presentation may inhibit acute rejection by decreasing host cytotoxic CD8+ T lymphocyte cell recognition and proliferation. Our specific aims are (1) to optimize adenoviral-mediated transduction of porcine vein grafts in vitro. (2) To determine the effect of AdICP47 mediated downregulation of MHC-I expression on acute rejection of venous allografts in vivo. The techniques of gene transfer developed in this research proposal may be applicable not only to vascular allografts but to the problems of transplant arteriopathy of cardiac allografts and rejection of other solid organs such as kidney and liver.